The present invention relates to crystalline erlotinib, including anhydrous as well as hydrated forms, processes for preparing them, pharmaceutical compositions thereof and their use in preparing erlotinib or pharmaceutical acceptable salts of erlotinib.
Erlotinib, chemically [6,7-bis(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine of formula 1
is a compound that inhibits the human epidermal growth factor receptor tyrosine kinase, also known as EGFR-TK, that is critical for growth of malignant cells. EGFR overexpression is associated with disease progression, and reduced survival. Erlotinib acts by blocking tyrosine kinase activity of EGFR-TK, resulting in inhibition of signaling pathway, and decreased growth of malignant tumors. Erlotinib is thus useful for the treatment of proliferative disorders such as cancers in humans. Erlotinib is marketed as its hydrochloride salt under such brand names as TARCEVA® (OSI Pharmaceuticals, Inc.) for treatment of certain lung cancers and pancreatic cancer.
WO 96/30347 and U.S. Pat. No. 5,747,498 teach quinazoline derivatives for treating hyperproliferative diseases such as cancers. Example 20 shows the formation of erlotinib free base and the subsequent conversion to the hydrochloride salt. Before the conversion to the salt, an organic phase containing the erlotinib was concentrated and the residue flash chromatographed on silica to obtain the free base as a pale yellow solid. This solid was then dissolved in a solvent and reacted with HCl to form the hydrochloride salt. There is no report of whether the solid erlotinib was crystalline.
European patent application EP 1044969 discloses processes for making erlotinib, its salts, and related compounds. Several examples make the hydrochloride salt (see examples 4, 7 and 9-11) and several make the mesylate salt (see examples 8 and 12). No mention is made in the examples of forming a solid erlotinib free base. Rather the solid forms are obtained by precipitation of the erlotinib salts.
Several patent publications disclose the existence of polymorphic forms of erlotinib salts. For example, WO 01/34574 discloses the existence of two polymorphic Forms of erlotinib hydrochloride which were designated as Form A and B. Form B is thermodynamically more stable than Form A. More recently WO 2004/072049 discloses the existence of another polymorph of erlotinib hydrochloride, designated as Form E, which is thought to have similar stability as Form B but with a higher solubility. The mesylate salt of erlotinib, with enhanced solubility compared to the hydrochloride, and its preparation is disclosed in WO 99/55683. Anhydrous erlotinib mesylate exists in three different polymorphic Forms designated Form A, B and C. Also a monohydrate of erlotinib mesylate and its use in the preparation of anhydrous mesylate Forms is disclosed.
While crystalline salts of erlotinib have been studied, it would be advantageous to be able to provide erlotinib in a solid, crystalline form.